These experiments were undertaken to assess the role of sorbitol dehydrogenase In mediating sorbitol pathway-linked neural and vascular dysfunction in rats with streptozocin-induced diabetes. 2-mehyl-4-[N,N dimethylsulfa-moyl-piperazino]-pyrimidine (S-0773), a putative inhibiter of sorbitol dehydrogenase, was given in the drinking water to control and diabetic rats. After 5 weeks of diabetes, glycosylated hemoglobin levels were in-creased twofold and were unaffected by 5-0773. Sorbitol levels in diabetic rats were increased 11- to 14 fold in ocular tissues and sciatic nerve; S-0773 increased sorbitol levels another 4-fold or more in these same tissues but had much smaller effects in other tissues. Diabetes-associated increases in fructose levels and lactate:pyruvate ratios in retina and in sciatic nerve were markedly attenuated by 5-0773. S-0773 also attenuated, but did not completely normalize, Impaired caudal nerve conduction and vascular dysfunction in ocular tissues, sciatic nerve, and aorta in diabetic rats. These observations, together with other evidence, suggest that sorbitol pathway-linked vascular dysfunction (in ocular tissues, peripheral nerve, and aorta) and electrophysiological dysfunction (in peripheral nerve) Induced by diabetes are more closely linked to increased oxidation of sorbitol to fructose than to putative osmotic effects of elevated sorbitol levels or redox and metabolic imbalances associated with reduction of glucose to sorbitol by aldose reductase.